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Interleukin-6 Wiki
'What is the role of Interleukin-6 in Intermediary Energy Metabolism in Skeletal Muscle?' ABSTRACT Intermediary energy metabolism (IEM) refers to all the interconnected ''chemical reactions that occur with the that occur within the cells of living organisms that sustain life '(Figure 1). While there are many pathways, perhaps the best known are those of glucose metabolism and fat metabolism in energy production. Due to the complexity of metabolism and the dynamic nature of a cell, there exists a need for regulation. Interleukin-6 is an inflammatory cytokine believed to be one such regulator of metabolism, albeit in an indirect manner. In this wiki, we provide a pathway in which IL5 stimulates fat oxidation (FAO) and glucose uptake (GU) via the AMPK activation. AMPK is known as a central regulator of intermediary metabolism and is stimulated by an intracellular signalling pathway when the Interleukin-6 receptor is activated (IL6R). With that being said, the impact that IL6 has on IEM is currently in contention. There are several articles arguing for and against IL6's role in stimulating FAO and GU, but we provide strong evidence that it does play a role in indirectly contributing to IEM. This wiki also describes the relationship between a cytokine released during the inflammatory response pathway and the metabolic disorders of diabetes and obesity. Interleukin-6 is an Inflammatory Cytokine Secreted During the Inflammatory Response Interleukin 6 is a pro-inflamatory cytokine that is released by T-cells and macrophages. When an infection or abnormal cells are detected by macrophages or T-cells, they release cytokines such as Interleukin 6 to fight against these infectious or abnormal cells. When interleukin 6 is call upon, it activates lymphocytes, increases antibody production and increases the temperature. These changes are induced to help kill the infectious cells in the body. Although IL-6 undoubtedly plays an important role in immunity in the body, it is not limited to this fuction. IL-6 also plays a role in metabolism. Key enzymes like adenosine monophosphate-activated protein kinase(AMPK) and glucose transported 4 (GLUT4) are regulated by IL6. IL-6 in skeletal muscle and adipose tissue is released and results in an increase in body temerature. Interleukin-6 Binds to the IL-6 Receptor and Activates Intracellular Signalling IL6 plays an important role in the immune response pathway, leading to the inflammatory response in humans. While IL6 concentration has been linked to aberrant metabolism and even cancer, it has been shown in recent literature the effects of the IL6 pathway in Interleukin-6 Stimulates AMP-activated Protein Kinase Majority of IL-6's activities are directed through AMP-activated Protein Kinase also known as AMPK (5). AMPK is an enzyme which maintains and regulates cellular energy (5). The means through with it maintains cellular energy is by playing a part in the regulation of processes such as lipolysis, lipogenesis and insulin secretion. IL-6 is allowed to play a role in these activites by regulating AMPK. A study performed by Andrew L. Carey and his team looks into and compirs the relation between IL-6 and AMPK (5). Glucose uptake was looked at for two cell types induced with insulin and/or IL-6. These cell types were ad Null which is a control and Ad AMPK AD cells which were AMPK dominant-negative-infected cells which are deficient in AMPK. A greater increse in glucose uptake was observed when cells were treated with insulin, IL-6 or both, than the AMPK deficient cells ('''Figure 2)(5). (Glucose uptake's relation with IL-6 will be explained in the next section, but keep in mind IL-6 dos increase glucose uptake. this exemplifies that IL-6 without AMPK will have a reduction in metabolic function (5). IL-6/AMPK is a Central Regulator of Glucose and Fat Metabolism A study by Gerrit van Hall looked at the relation of fatty acid (FA) levels in compairson to recombinant Interleukin 6 addition. FA was discovered to increase in the plasma (Figure 3)(6). The control had a stable level of FA in the plasma whereas the FA in IL-6 induced samples experienced increases in FA levels. This suggests that IL does indeed increase lipolysis making it a possible novel lipolytic factor (6). In Gerrit van Hall's study, high and low additions of IL-6 was tested to see the difference between the two. They both relatively had similar FA levles (Figure 3), however high levels of IL-6 addition resulted in some immune response symptoms such as slight shivering and discomfort (6). These results in conjunction to a study done by Stouthard et al, find that overloading on IL-6 doesnt not lead to even higher lipolysis (6). In Stouthard's study even higher amounts of IL-6 than Gerrit van Hall's study was administered on patients with metastatic renal cell cancer. The FA levels however were suprisingly similar to that of Gerrit van Hall's subjects leading to the conclusion that any concentration of above 140 pg/ml of IL-6 has the same effect on FA levels (6). Any higher will only increase the sickness and discomport feelings however will not increase anyfurther lipolysis levels (6). Another thing noted by Gerrit van Hall is that IL-6 does not directly affect FA lipolysis (6). FA levels spiked around 2.5 hours follwing infussion of IL-6. Also FA goes back to normal after 3 hours of cessation of infusion. This sugges that IL-6 is involved in an indirect pathway to increase lipolysis. This indirect pathway has IL-6 affecting other molecules which directly affect the oxidation of FA (6). Also looking at Figure 2 we see that glucose is indeed unregulated by th addition of IL-6. This process does occur through the regulation of AMPK by IL-6 (5). The key change to upregulate glucose is through the translocation of GLUT4 from intracellular pools to plasma membrane which is directly stimulated by AMPK (5). GLUT4 is a trans-membrane protein that imports glucose from the bloodstream into cells. By bringing glucose into the cell, glucose concentration goes up in the cell and glycolysis will consequently increase. Glycolysis will produce pyruvate molecules from the glucose which will then in trun be converted to acetyl chains. These acetyl chains go through the kreb's cycle and ends at the electron transport chain. Interleukin-6 Receptor is a Potential Target for Type II Diabetes and Obesity Diabetes is a disease caused by abnormalities in the glucose metabolism pathway (3). Individuals with diabetes have extreemly high levels of blood glucose levels, also known as hyperglycemia (3). Food consumed is converted to glucose which is then transported from the bloodstream to adipose and muscle cells. In diabetic patients the transportation of glucose into fat and muscle cells is difficult due to insulin related problems (3). Type 1 diabetes patients do not produce insulin whereas type 2 diabetes involves insulin resistance. The lack of insulin binding is deterimental as insulin plays a major factor in glucose intake.Insulin very closely directs GLUT4 to join the plasma membrane (2)(3). During inactivity of insulin, GLUT4 is sequestered in intracellular vesicles, however when insulin is active, GLUT4 merges into the plasma membrane (1)(2). This transporter protein allows the body to reduce blood glucose levels by transporting glucose from the bloodstream into cells (4). Accumulation of glucose is what leads to hyperglycemia leading to adverse conditions in the body. References 1. Abel, ED; Peroni, O; Kim, JK; Kim, YB; Boss, O; Hadro, E; Minnemann, T; Shulman, GI; Kahn, BB. Adipose-selective targeting of the GLUT4 gene impairs insulin action in muscle and liver. Nature, 2000, 409: 729-733 2. Stenbit, EB; Tsao, TS; Li, J, Burcelin, R; Geenen, DL; Factor, SM; Houseknecht, K; Katz, EB; Charron, MJ. Glut4 heterozygous knockout mice develop muscle insulin resistance and diabetes. Nat med. 1997, 10: 1096-101 3. Sarwar, N; Gao, P; Seshasai, SR; Gobin, R; Kaptoge, S; Di Angelantonio, E; Ingelsson, E; Lawlor, DA; Selvin, E; Stampfer, M; Stehouwer, CD; Lewington, S; Pennells, L; Thompson, A; Sattar, N; White, IR; Ray, KK; Danesh, J. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet. 2010'', '375(9733): 2215-22 4. ''Mcauley, DF; Nugent, AG, McGurk, C; Maguire, S; Hayes, JR; Johnston, GD. Vasoconstriction to endogenous endothelin-1 is impaired in patients with Type ll diabetes mellitus. ''Clinical Science. '''2000. 99: 175-179 5. Carey, AL; Steinberg, GR; Macaulay, SL; Thomas, WG; Holmes, AG; Ramm, G; Prelovsek, O; Hohnen-Behrens, C; Watt, MJ; James, DE; Kemp, BE; Pedersen, BK; Febbraio, MA. Interleukin-6 increases insulin-stimulated glucose disposal in humans and glucose uptake and fatty acid oxidation in vitro via AMP-Activated Protein Kinase. Diabetes. 2006.' '''40: 2688-2697 6. Hall, GV; Steensberg, A; Sacchetti, M; Frischer, C; Keller, C; Schjerling, P; Hiscock, N; Moller, K; Saltin, B; Febbraio, MA; Pedersen, BK. Interlukin-6 stimulates lipolysis and fat oxidation in humans. ''JCEM. 2003. 88(7):3005-3010 Category:Browse